Circ J 2008; 72: 399–403

Multiple Yellow Plaques Assessed by Angioscopy With Quantitative Colorimetry in Patients With Myocardial Infarction

Shigenobu Inami, MD*; Fumiyuki Ishibashi, MD*,**; Sergio Waxman, MD**; Kentaro Okamatsu, MD*; Koji Seimiya, MD*; Masamichi Takano, MD*; Ryota Uemura, MD*; Junko Sano, MD*; Kyoichi Mizuno, MD*

Background Multiple angioscopic yellow plaques are associated with diffuse atherosclerotic plaque, and may be prevalent in patients with myocardial infarction (MI), so in the present study the yellow plaques in the coronary of patients with MI was evaluated using quantitative colorimetry, and compared with those of patients with stable angina (SA). Methods and Results In the recorded angioscopic images of 3 coronary vessels in 29 patients (15 patients with MI, 14 with SA), yellow plaques were determined as visually yellow regions with b* value >0 (yellow color intensity) measured by the quantitative colorimetric method. A total of 90 yellow plaques were identified (b*=19.35±8.3, 3.05–45.35). Yellow plaques were significantly more prevalent in 14 (93%) of 15 culprit lesions of MI as compared with 8 (57%) of 14 of SA (p=0.03). In non-culprit segments, yellow plaques were similarly prevalent in 13 (87%) patients with MI and 11 (79%) with SA (p=0.65). Overall, multiple (≥2) yellow plaques were prevalent in 13 (87%) patients with MI, similar to the 10 (71%) with SA (p=0.38). The number of yellow plaques was significantly higher in patients with MI (3.8±1.9) than in those with SA (2.4±1.6, p=0.03). Conclusion The present study suggests that patients with MI tend to have diffuse atherosclerotic plaque in their coronary arteries. (Circ J 2008; 72: 399–403) Key Words: Arteriosclerosis; Coronary disease; Imaging; Plaque

atients with myocardial infarction (MI) may have dif- spectively collected images and data from patients in Chiba fuse coronary plaque.1–4 Yellow plaque seen during Hokusoh Hospital, Nippon Medical School, Chiba, Japan. P coronary angioscopy is thought to be surrogates for Among 327 patients who underwent coronary angioscopy superficial intimal lipids.5–9 A recent study of ex-vivo coro- between 1998 and 2003, 29 non-consecutive patients (15 nary segments reported that yellow plaques, determined by MI, 14 SA) were selected for the present analysis based on angioscopy with quantitative colorimetry,10 were frequently the following criteria: (1) the culprit lesion was clearly iden- identified as several yellow spots on a single mass of dif- tified by as the most significantly stenotic fuse atherosclerotic plaque, and that the number of yellow lesion in a coronary , which correlated with the pres- plaques correlated with the surface area or the burden of ence of ST segment changes on a 12-lead electrocardiogram atherosclerotic plaque.11 Therefore, multiple yellow plaques (ECG) or with a perfusion defect revealed by radionuclide may be prevalent in the coronary arteries of patients with scan; (2) angioscopic images of 3 coronary arteries were MI. Although a prior angioscopic study has reported this,12 available; (3) the patient had never previously undergone such findings have not been explored in other patient popu- either percutaneous coronary intervention or coronary artery lations. So, to determine whether multiple yellow plaques bypass grafting before the angioscopic procedure; (4) the are prevalent in other Japanese patients with MI, we used patient had never experienced prior coronary syndromes; angioscopy with quantitative colorimetry to examine pa- (5) the patient had not been undergoing continuous hemo- tients with MI, and compared the results with those from dialysis because of chronic renal failure; and (6) the patient patients who had stable angina (SA). had neither acute nor chronic inflammatory disease. Acute MI was defined by typical chest pain, ST segment elevation on the 12-lead ECG and serum creatine kinase elevation Methods greater than twice the upper limit of normal. Angioscopy The present study was a retrospective analysis of pro- was performed as previously described13,14 within 6 weeks from the onset of MI. SA was defined as a positive stress (Received May 7, 2007; revised manuscript received September 25, test and no change in the frequency, duration or intensity of 2007; accepted November 1, 2007) symptoms that had persisted for >4 weeks. Written informed *Chiba-Hokusoh Hospital, Nippon Medical School, Chiba, Japan, consent approved by the Institutional Review Board was **Lahey Clinic Medical Center, Burlington, MA, USA given by all patients. Mailing address: Fumiyuki Ishibashi, MD, Lahey Clinic Medical Cen- ter, 41 Mall Road, Burlington, MA, 01805, USA. E-mail: lotuslazor A laptop computer (Macintosh Powerbook G4, Apple [email protected] Computer, Inc, CA, USA) was connected to the S (Y/C) All rights are reserved to the Japanese Circulation Society. For per- signal output of a videotape player via an analog/digital missions, please e-mail: [email protected] converter (ADVC-100, Canopus Co, Kobe, Japan) with a

Circulation Journal Vol.72, March 2008 400 INAMI S et al.

Table 1 Patients’ Characteristics

Myocardial infarction Stable angina p value (n=15) (n=14) Age, years 62.3±7.9 60.6±12.6 0.66 Males 13 11 0.65 Hypertension 10 9 0.89 Hyperlipidemia 11 11 >0.99 Diabetes mellitus 1 3 0.32 Cigarette smoking 9 8 0.87 Obesity 6 5 0.81 Family history 6 4 0.51 Culprit lesion, LAD/LCX/RCA 11/3/1 7/3/4 – Length of observed artery, mm LAD 61±11 63±9 0.58 LCX 41±15 37±9 0.25 RCA 68±29 63±16 0.64 Statin use (>4 weeks before procedure) 1 1 >0.99

Values are n and the mean±standard deviation. LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery.

6-pin IEEE 1394 connector. The display of the laptop the quantified color (b* value) in the respective angioscopic computer was adjusted to the color temperature=CIE D65 region. (based on the color temperature of xenon lamplight) and In the present analysis angioscopic yellow plaque was de- the gamma=2.2 (based on the definition in NTSC system) fined as a visually yellow region with a quantified b* value for the better visualization of image color. Customized soft- >0 (yellow color intensity). Because high yellow color in- ware (CSVEC-analyzer, ver.1.1.0d1) installed in the laptop tensity (HYCI, b* value ≥23) was associated with lipid computer was used for quantitative colorimetry, in which cores underneath thin fibrous caps in ex-vivo atherosclerotic the known L*a*b* color space was adopted to express the plaques of carotid/femoral arteries in our previous study,10 color (available at: http://en.wikipedia.org/wiki/Lab_color_ a HYCI region was also analyzed. space). Continuous variables are expressed as mean±standard All image analysis was performed on the laptop computer. deviation. Group differences or correlation were assessed Two observers reviewed the angioscopy movie images. In with the chi-square test or the Fisher exact probability test. culprit lesions, plaque color (yellow vs white) was visually Student’s t-test and the Mann-Whitney U test were used for determined as previously described.13,14 In non-culprit seg- continuous variables. The relationship between 2 continuous ments, yellow plaques were visually identified. For quantita- variables was assessed with Pearson’s correlation coefficient. tive colorimetry, a total of 97 angioscopic coronary regions A p-value of <0.05 was considered statistically significant. were determined in all culprit lesions, and yellow plaques in non-culprit segments, as follows: culprit of MI (n=15); non-culprit of MI (n=43); culprit of SA (n=14); and non- Results culprit of SA (n=25). All images showing angioscopic re- The clinical characteristics of the patients are shown in gions were saved as single-frame images (bitmap format) in Table1. A total of 90 yellow plaques were identified (b*= the laptop computer. 19.35±8.3, 3.05–45.35). Yellow plaques were significantly Two investigators performed the quantitative colorimetric more prevalent in 14 (93%) of 15 culprit lesions of MI as analysis separately and independently. On the saved image, compared with 8 (57%) of 14 of SA (p=0.03). In non-culprit a region of interest (ROI) for each coronary region was out- segments, yellow plaques were similarly prevalent in 13 lined in freehand with the computer cursor and demarcated (87%) patients with MI and 11 (79%) with SA (p=0.65, as follows: (1) a homogeneous white or yellow region with- Fig1). Overall, multiple (≥2) yellow plaques were preva- in the plaque; (2) a yellow region within a mixed yellow and lent in 13 (87%) patients with MI, which was similar to the white plaque; or (3) a clearly deeper yellow region within a 10 (71%) with SA (p=0.38, Fig2). The number of yellow heterogeneous yellow plaque. Overlying thrombus was ex- plaques in the coronary arteries was significantly higher in cluded. The mean value of brightness L* was measured to patients with MI (3.8±1.9) than in those with SA (2.4±1.6, confirm that it was within the established optimal range of p=0.03, Fig3). The number was significantly higher in the L* values.10 If brightness L* in the ROI was not optimal, a culprit artery of MI (1.9±1.2) than in the culprit artery of SA different single-frame image was chosen and the process (0.9±0.6, p=0.01); however, it was similar in non-culprit repeated until optimal brightness L* was confirmed in the arteries (1.8±1.1 vs 1.4±1.2, p=0.39, Fig4). ROI. Then, for each ROI, pixels without optimal L* values HYCI regions were identified in 34 (38%) of 90 yellow were excluded, and b* values were obtained for the remain- plaques, and were significantly more prevalent in 10 (67%) ing pixels and expressed as the color of the ROI. On the culprit lesions of MI than in 4 (21%) of SA (p=0.02). In same single-frame image, the ROI was retraced and the non-culprit segments, HYCI regions were identified in 8 measurement of color was repeated. Intra-observer agree- (53%) patients with MI and in 3 (21%) with SA (p=0.12). ment for the b* value was r=0.965 for the first and r=0.912 Overall, HYCI regions were significantly more prevalent for the second observer (p<0.0001). Interobserver agree- in 11 (73%) patients with MI than in 5 (36%) with SA ment was analyzed using the mean value of 2 measurements (p=0.04). Multiple (2–7) HYCI regions were identified in 7 by each observer, and was r=0.908 (p<0.0001). The mean (47%) patients with MI and 3 (21%) with SA, respectively value of the 4 analyses by the 2 observers was expressed as (p=0.24). The number of HYCI regions in the culprit artery

Circulation Journal Vol.72, March 2008 Yellow Plaque in MI 401

Fig 1. Yellow plaques in patients with myocardial infarction or Fig3. Number of yellow plaques in the coronary arteries of patients stable angina in the culprit lesion (Left) or non-culprit segment with myocardial infarction or stable angina. (Right).

Fig2. Prevalence of multiple yellow plaques in the coronary arteries Fig4. Number of yellow plaques in patients with myocardial infarc- of patients with myocardial infarction or stable angina. tion or stable angina in either the culprit (Left) or non-culprit (Right) artery. was 0.9±0.9 in MI and 0.4±0.5 in SA (p=0.05), and was the present angioscopic study suggest that patients with MI 0.6±1.1 and 0.4±0.8 in non-culprit arteries, respectively tend to have diffuse atherosclerotic plaque in their coronary (p=0.51). arteries. Atherosclerosis has a diffuse nature,1 and pathologic The number of yellow plaques was significantly higher and studies have suggested that in the 16 patients with HYCI regions (4.0±1.6) than in the patients experiencing acute coronary syndromes may have 13 without (2.0±1.6, p=0.002). diffuse atherosclerotic plaque in their coronary arteries,2–3 which concurs with our findings. Focal atheromas can be commonly seen in diffuse atherosclerotic plaques,1,15 which Discussion is compatible with the association of a HYCI region with a We found that multiple yellow plaques, determined by relatively increased number of yellow plaques. Furthermore, angioscopy with quantitative colorimetry, were prevalent in a recent intravascular ultrasound study also demonstrated the coronary arteries of patients with MI, as well as SA, and that the lipid core and plaque are increased in patients with that the number of yellow plaques was significantly higher acute coronary syndromes.4 The results of the present study in patients with MI as compared with those with SA. are comparable with those from a prior angioscopic study Given the positive correlation of the number of angio- by Asakura et al,12 in which multiple yellow plaques were scopic yellow plaques with the surface area or burden of prevalent not only in culprit lesions but also in non-culprit atherosclerotic plaque in coronary segments,11 the results of segments of 20 patients with MI, although the present

Circulation Journal Vol.72, March 2008 402 INAMI S et al. study results imply that there may be some heterogeneity of onset.31,32 Lastly, coronary angioscopy as a routine imaging atherosclerotic plaque between culprit and non-culprit technique is impractical because of its invasive nature.33 arteries. Obviously, a systemic approach to the coronary Nevertheless, it could be used as a clinical research tool, arteries is essential in the treatment of patients with MI, as because it is a unique modality for detecting thrombi in well as those with SA. Furthermore, the results of the pres- vivo34 and further research with its use could be of value in ent study endorse that there is a threshold of the extent of clarifying the association of high-risk coronaries with acute coronary plaque, which may be a possible marker of future MI. MI. Ohtani et al revealed an association of an increased number of yellow plaques with future cardiovascular events,16 which is similar to the findings of the present study. Conclusion Multivessel disease detected by angiography is commonly The results of the present angioscopic study suggest that associated with future cardiac events, and a previous angio- patients with MI tend to have diffuse atherosclerotic plaque graphic study has suggested that diffuse plaque involve- in their coronary arteries. ment may be a useful marker for stratifying high-risk pa- tients.17 Therefore, using some non-invasive method of Acknowledgments assessing the extent of coronary plaque, such as computed This study was supported in part by Research Grants from Fukuda tomography,18 would be ideal for better primary prevention Kinenn Foundation (to F.I.) and Research Grants for Cardiovascular of MI. Disease (H15–05 and H16–011) from the Japanese Ministry of Health, The results of the present study emphasize that the tem- Labor and Welfare (to K.M.). poral and spatial prevalence of lipid core regions underneath thin fibrous caps in patients with MI is still a matter for References research and potentially of importance for the better sec- 1. Libby P, Ridker PM. Inflammation and atherothrombosis from popu- ondary prevention of MI.19,20 The angioscopic finding of lation biology and bench research to clinical practice. J Am Coll Car- multiple yellow plaques in the coronary arteries does not diol 2006; 48: A33–A46. 2. Roberts WC. Diffuse extent of coronary atherosclerosis in fatal coro- necessarily represent the presence of multiple coronary nary artery disease. Am J Cardiol 1990; 65: 2F–6F. regions that have a higher probability of plaque rupture, be- 3. Nissen SE. 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